Automatic neural stimulation modulation based on motion and physiological activity

ABSTRACT

An embodiment of a method uses an implantable device to deliver a heart failure therapy to a patient. The device is used to sense unintended motion of the patient caused by the neural stimulation and identify a sensed motion level for the sensed unintended motion, and to sense physiological activity of the patient, different than the sensed motion, and identify a sensed physiological activity level. Delivering the heart failure therapy includes delivering neural stimulation through an electrode to a neural target in an autonomic nervous system of the patient using the implantable device. The sensed motion level, the sensed physiological activity level, and the programmed mapping are used to determine the neural stimulation intensity level of the neural stimulation to be delivered for the motion level.

CLAIM OF PRIORITY

This application is a continuation-in-part of and claims the benefit ofpriority under 35 U.S.C. §120 to U.S. patent application Ser. No.11/558,083, entitled “Automatic Neural Stimulation Modulation Based OnActivity,” filed on Nov. 9, 2006, published as US 2007/0142864 on Jun.21, 2007, now U.S. Pat. No. 7,783,353, which application is acontinuation-in-part and claims the benefit of priority under 35 U.S.C.§120 of U.S. patent application Ser. No. 10/746,846, filed on Dec. 24,2003, entitled “Automatic Baroreflex Modulation Based on CardiacActivity,” published as US 2005/0149132 on Jul. 7, 2005, abandoned, eachof which are herein incorporated by reference in their entirety.

CROSS REFERENCE TO RELATED APPLICATIONS

The following commonly assigned U.S. patent applications are related,are all filed on Dec. 24, 2003 and are all herein incorporated byreference in their entirety: “Baroreflex Stimulation System to ReduceHypertension,” U.S. patent application Ser. No. 10/746,134, published asUS 2005/0149128 on Jul. 7, 2005, now U.S. Pat. No. 7,643,875; “SensingWith Compensation for Neural Stimulator,” U.S. patent application Ser.No. 10/746,847, published as US 2005/0149133 on Jul. 7, 2005, abandoned;“Implantable Baroreflex Stimulator with Integrated Pressure Sensor,”U.S. patent application Ser. No. 10/745,921, published as US2005/0149143 on Jul. 7, 2005, now U.S. Pat. No. 7,869,881; “AutomaticBaroreflex Modulation Responsive to Adverse Event,” U.S. patentapplication Ser. No. 10/745,925, published as US 2005/0149127 on Jul. 7,2005, now U.S. Pat. No. 7,509,166; “Baroreflex Modulation to GraduallyIncrease Blood Pressure,” U.S. patent application Ser. No. 10/746,845,published as US 2005/0149131 on Jul. 7, 2005, now U.S. Pat. No.7,486,991; “Baroreflex Stimulation to Treat Acute MyocardialInfarction,” U.S. patent application Ser. No. 10/745,920, published asUS 2005/0149126 on Jul. 7, 2005, now U.S. Pat. No. 7,460,906;“Baropacing and Cardiac Pacing to Control Output,” U.S. patentapplication Ser. No. 10/746,135, published as US 2005/0149129 on Jul. 7,2005; “Baroreflex Stimulation Synchronized to Circadian Rhythm,” U.S.patent application Ser. No. 10/746,844, published as US 2005/0149130 onJul. 7, 2005, now U.S. Pat. No. 7,706,884; “A Lead for Stimulating theBaroreflex in the Pulmonary Artery,” U.S. patent application Ser. No.10/746,861, published as US 2005/0149156 on Jul. 7, 2005, now U.S. Pat.No. 8,024,050; and “A Stimulation Lead for Stimulating the Baroreceptorsin the Pulmonary Artery,” U.S. patent application Ser. No. 10/746,852,published as 2005/0149155 on Jul. 7, 2005, now U.S. Pat. No. 8,126,560.

TECHNICAL FIELD

This application relates generally to implantable medical devices and,more particularly, to automatically modulating neural stimulation basedon activity.

BACKGROUND

Implanting a chronic electrical stimulator, such as a cardiacstimulator, to deliver medical therapy(ies) is known. Examples ofcardiac stimulators include implantable cardiac rhythm management (CRM)device such as pacemakers, implantable cardiac defibrillators (ICDs),and implantable devices capable of performing pacing and defibrillatingfunctions.

CRM devices are implantable devices that provide electrical stimulationto selected chambers of the heart in order to treat disorders of cardiacrhythm. An implantable pacemaker, for example, is a CRM device thatpaces the heart with timed pacing pulses. If functioning properly, thepacemaker makes up for the heart's inability to pace itself at anappropriate rhythm in order to meet metabolic demand by enforcing aminimum heart rate. Some CRM devices synchronize pacing pulses deliveredto different areas of the heart in order to coordinate the contractions.Coordinated contractions allow the heart to pump efficiently whileproviding sufficient cardiac output.

Heart failure refers to a clinical syndrome in which cardiac functioncauses a below normal cardiac output that can fall below a leveladequate to meet the metabolic demand of peripheral tissues. Heartfailure may present itself as congestive heart failure (CHF) due to theaccompanying venous and pulmonary congestion. Heart failure can be dueto a variety of etiologies such as ischemic heart disease.

Hypertension is a cause of heart disease and other related cardiacco-morbidities. Hypertension occurs when blood vessels constrict. As aresult, the heart works harder to maintain flow at a higher bloodpressure, which can contribute to heart failure. A large segment of thegeneral population, as well as a large segment of patients implantedwith pacemakers or defibrillators, suffer from hypertension. The longterm mortality as well as the quality of life can be improved for thispopulation if blood pressure and hypertension can be reduced. Manypatients who suffer from hypertension do not respond to treatment, suchas treatments related to lifestyle changes and hypertension drugs.

A pressoreceptive region or field is capable of sensing changes inpressure, such as changes in blood pressure. Pressoreceptor regions arereferred to herein as baroreceptors, which generally include any sensorsof pressure changes. For example, baroreceptors include afferent nervesand further include sensory nerve endings that are sensitive to thestretching of the wall that results from increased blood pressure fromwithin, and function as the receptor of a central reflex mechanism thattends to reduce the pressure. Baroreflex functions as a negativefeedback system, and relates to a reflex mechanism triggered bystimulation of a baroreceptor. Increased pressure stretches bloodvessels, which in turn activates baroreceptors in the vessel walls.Activation of baroreceptors naturally occurs through internal pressureand stretching of the arterial wall, causing baroreflex inhibition ofsympathetic nerve activity (SNA) and a reduction in systemic arterialpressure. An increase in baroreceptor activity induces a reduction ofSNA, which reduces blood pressure by decreasing peripheral vascularresistance.

The general concept of stimulating afferent nerve trunks leading frombaroreceptors is known. For example, direct electrical stimulation hasbeen applied to the vagal nerve and carotid sinus. Research hasindicated that electrical stimulation of the carotid sinus nerve canresult in reduction of experimental hypertension, and that directelectrical stimulation to the pressoreceptive regions of the carotidsinus itself brings about reflex reduction in experimental hypertension.

Electrical systems have been proposed to treat hypertension in patientswho do not otherwise respond to therapy involving lifestyle changes andhypertension drugs, and possibly to reduce drug dependency for otherpatients.

SUMMARY

Various aspects and embodiments of the present subject matter use atleast one parameter related to activity, such as a motion monitorconfigure to sense motion of the patient and a physiological activitymonitor configured to sense a physiological activity of the patient thatis different than the sensed motion, to automatically modulate neuralstimulation. This document discusses baroreflex stimulation as anexample of neural stimulation. Those of ordinary skill in the art willunderstand, upon reading and comprehending this disclosure, that othertypes of neural stimulation can be modulated based on activity.

An embodiment of a system for providing neural stimulation to a neuraltarget in an autonomic nervous system of a patient for a heart failuretherapy to the patient, comprises a motion monitor and a physiologicalactivity monitor. The motion monitor is configured to sense motion ofthe patient and provide a signal indicative of a sensed motion level,and configured to sense an unintended motion caused by the neuralstimulation. The physiological activity monitor is configured to sense aphysiological activity of the patient different than the sensed motion,and configured to provide a signal indicative of a sensed physiologicalactivity level. The system further comprises an electrode configured foruse to deliver neural stimulation to the neural target, a neuralstimulator, and a controller. The neural stimulator includes a pulsegenerator configured to deliver a neural stimulation signal through theelectrode to provide the neural stimulation to the neural target for theheart failure therapy, and configured to deliver the neural stimulationsignal as a series of pulses with different programmed burst patternsfor different stimulation intensity levels. The neural stimulatorfurther includes a modulator configured to modulate the neuralstimulation signal to change an intensity level of the neuralstimulation. The controller is configured to store a mapping of aplurality of physiological activity levels and a plurality of motionlevels for the unintended motion caused by the neural stimulation to aplurality of neural stimulation intensity levels. The controller isconfigured to receive both the signal indicative of the physiologicalactivity level and the signal indicative of the sensed motion level andto control the modulator to deliver the neural stimulation at intensitylevels mapped to the sensed physiological activity level and the sensedmotion level.

According to an embodiment of a method for using an implantable deviceto deliver a heart failure therapy to a patient, an implantable deviceis used to sense unintended motion of the patient caused by the neuralstimulation and identify a sensed motion level for the sensed unintendedmotion, and to sense physiological activity of the patient, differentthan the sensed motion, and identify a sensed physiological activitylevel. The method includes delivering the heart failure therapy.Delivering the heart failure therapy includes delivering neuralstimulation through an electrode to a neural target in an autonomicnervous system of the patient using the implantable device. The methodincludes determining a neural stimulation intensity level for the heartfailure therapy using a programmed mapping of a plurality of motionlevels and a plurality of physiological activity levels to a pluralityof neural stimulation intensity levels. Determining the neuralstimulation intensity level includes using the sensed motion level, thesensed physiological activity level, and the programmed mapping todetermine the neural stimulation intensity level of the neuralstimulation to be delivered for the motion level.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects will be apparent to persons skilled in the art upon reading andunderstanding the following detailed description and viewing thedrawings that form a part thereof, each of which are not to be taken ina limiting sense. The scope of the present invention is defined by theappended claims and their equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B illustrate neural mechanisms for peripheral vascularcontrol.

FIGS. 2A-2C illustrate a heart.

FIG. 3 illustrates baroreceptors and afferent nerves in the area of thecarotid sinuses and aortic arch.

FIG. 4 illustrates baroreceptors in and around the pulmonary artery.

FIG. 5 illustrates baroreceptor fields in the aortic arch, theligamentum arteriosum and the trunk of the pulmonary artery.

FIG. 6 illustrates a known relationship between respiration and bloodpressure when the baroreflex is stimulated.

FIG. 7 illustrates a blood pressure response to carotid nervestimulation in a hypertensive dog during 6 months of intermittentcarotid nerve stimulation.

FIG. 8 illustrates a system including an implantable medical device(IMD) and a programmer, according to various embodiments of the presentsubject matter.

FIG. 9 illustrates an implantable medical device (IMD) such as shown inthe system of FIG. 8, according to various embodiments of the presentsubject matter.

FIGS. 10A-10C illustrate a baroreceptor stimulation lead with anintegrated pressure sensor (IPS), according to various embodiments ofthe present subject matter.

FIG. 11 illustrates an implantable medical device (IMD) such as shown inFIG. 8 having a neural stimulator (NS) component and cardiac rhythmmanagement (CRM) component, according to various embodiments of thepresent subject matter.

FIG. 12 illustrates a system including a programmer, an implantableneural stimulator (NS) device and an implantable cardiac rhythmmanagement (CRM) device, according to various embodiments of the presentsubject matter.

FIG. 13 illustrates an implantable neural stimulator (NS) device such asshown in the system of FIG. 12, according to various embodiments of thepresent subject matter.

FIG. 14 illustrates an implantable cardiac rhythm management (CRM)device such as shown in the system of FIG. 12, according to variousembodiments of the present subject matter.

FIG. 15 illustrates a programmer such as illustrated in the systems ofFIGS. 8 and 12 or other external device to communicate with theimplantable medical device(s), according to various embodiments of thepresent subject matter.

FIGS. 16A-16D illustrate a system and methods to prevent interferencebetween electrical stimulation from a neural stimulator (NS) device andsensing by a cardiac rhythm management (CRM) device, according tovarious embodiments of the present subject matter.

FIG. 17 illustrates a system to modulate neural stimulation such asbaroreflex stimulation, according to various embodiments of the presentsubject matter.

FIGS. 18A-18E illustrate methods for modulating neural stimulation suchas baroreceptor stimulation based on an activity parameter, according tovarious embodiments of the present subject matter.

FIGS. 19A-19B illustrate methods for modulating baroreceptor stimulationbased on a respiration parameter, according to various embodiments ofthe present subject matter.

FIGS. 20A-20E illustrate circadian rhythm.

FIG. 21 illustrates a method for modulating baroreceptor stimulationbased on circadian rhythm, according to various embodiments of thepresent subject matter.

FIG. 22A-B illustrate methods for modulating baroreceptor stimulationbased on a cardiac output parameter, according to various embodiments ofthe present subject matter.

FIG. 23 illustrates a method for modulating baroreceptor stimulation toreverse remodel stiffening, according to various embodiments of thepresent subject matter.

FIGS. 24A-24B illustrate a system and method to detect myocardialinfarction and perform baropacing in response to the detected myocardialinfarction, according to various embodiments of the present subjectmatter.

DETAILED DESCRIPTION

The following detailed description of the present subject matter refersto the accompanying drawings which show, by way of illustration,specific aspects and embodiments in which the present subject matter maybe practiced. These embodiments are described in sufficient detail toenable those skilled in the art to practice the present subject matter.Other embodiments may be utilized and structural, logical, andelectrical changes may be made without departing from the scope of thepresent subject matter. References to “an”, “one”, or “various”embodiments in this disclosure are not necessarily to the sameembodiment, and such references contemplate more than one embodiment.The following detailed description is, therefore, not to be taken in alimiting sense, and the scope is defined only by the appended claims,along with the full scope of legal equivalents to which such claims areentitled.

Hypertension, Baroreflex, Heart Failure and Cardiac Remodeling

A brief discussion of hypertension and the physiology related tobaroreceptors is provided to assist the reader with understanding thisdisclosure. This brief discussion introduces hypertension, the autonomicnervous system, and baroreflex.

Hypertension is a cause of heart disease and other related cardiacco-morbidities. Hypertension generally relates to high blood pressure,such as a transitory or sustained elevation of systemic arterial bloodpressure to a level that is likely to induce cardiovascular damage orother adverse consequences. Hypertension has been arbitrarily defined asa systolic blood pressure above 140 mm Hg or a diastolic blood pressureabove 90 mm Hg. Hypertension occurs when blood vessels constrict. As aresult, the heart works harder to maintain flow at a higher bloodpressure. Consequences of uncontrolled hypertension include, but are notlimited to, retinal vascular disease and stroke, left ventricularhypertrophy and failure, myocardial infarction, dissecting aneurysm, andrenovascular disease.

The automatic nervous system (ANS) regulates “involuntary” organs, whilethe contraction of voluntary (skeletal) muscles is controlled by somaticmotor nerves. Examples of involuntary organs include respiratory anddigestive organs, and also include blood vessels and the heart. Often,the ANS functions in an involuntary, reflexive manner to regulateglands, to regulate muscles in the skin, eye, stomach, intestines andbladder, and to regulate cardiac muscle and the muscle around bloodvessels, for example.

The ANS includes the sympathetic nervous system and the parasympatheticnervous system. The sympathetic nervous system is affiliated with stressand the “fight or flight response” to emergencies. Among other effects,the “fight or flight response” increases blood pressure and heart rateto increase skeletal muscle blood flow, and decreases digestion toprovide the energy for “fighting or fleeing.” The parasympatheticnervous system is affiliated with relaxation and the “rest and digestresponse” which, among other effects, decreases blood pressure and heartrate, and increases digestion to conserve energy. The ANS maintainsnormal internal function and works with the somatic nervous system.

Various embodiments refer to the effects that the ANS has on the heartrate and blood pressure, including vasodilation and vasoconstriction.The heart rate and force is increased when the sympathetic nervoussystem is stimulated, and is decreased when the sympathetic nervoussystem is inhibited (the parasympathetic nervous system is stimulated).FIGS. 1A and 1B illustrate neural mechanisms for peripheral vascularcontrol. FIG. 1A generally illustrates afferent nerves to vasomotorcenters. An afferent nerve conveys impulses toward a nerve center. Avasomotor center relates to nerves that dilate and constrict bloodvessels to control the size of the blood vessels. FIG. 1B generallyillustrates efferent nerves from vasomotor centers. An efferent nerveconveys impulses away from a nerve center.

Stimulating the sympathetic and parasympathetic nervous systems can haveeffects other than heart rate and blood pressure. For example,stimulating the sympathetic nervous system dilates the pupil, reducessaliva and mucus production, relaxes the bronchial muscle, reduces thesuccessive waves of involuntary contraction (peristalsis) of the stomachand the motility of the stomach, increases the conversion of glycogen toglucose by the liver, decreases urine secretion by the kidneys, andrelaxes the wall and closes the sphincter of the bladder. Stimulatingthe parasympathetic nervous system (inhibiting the sympathetic nervoussystem) constricts the pupil, increases saliva and mucus production,contracts the bronchial muscle, increases secretions and motility in thestomach and large intestine, and increases digestion in the smallintention, increases urine secretion, and contracts the wall and relaxesthe sphincter of the bladder. The functions associated with thesympathetic and parasympathetic nervous systems are many and can becomplexly integrated with each other. Thus, an indiscriminatestimulation of the sympathetic and/or parasympathetic nervous systems toachieve a desired response, such as vasodilation, in one physiologicalsystem may also result in an undesired response in other physiologicalsystems.

Baroreflex is a reflex triggered by stimulation of a baroreceptor. Abaroreceptor includes any sensor of pressure changes, such as sensorynerve endings in the wall of the auricles of the heart, cardiac fatpads, vena cava, aortic arch and carotid sinus, that is sensitive tostretching of the wall resulting from increased pressure from within,and that functions as the receptor of the central reflex mechanism thattends to reduce that pressure. Additionally, baroreflex pathways includeafferent nerve trunks, such as the vagus, aortic and carotid nerves,leading from the sensory nerve endings. Baroreflex stimulation inhibitssympathetic nerve activity (stimulates the parasympathetic nervoussystem) and reduces systemic arterial pressure by decreasing peripheralvascular resistance and cardiac contractility. Baroreceptors arenaturally stimulated by internal pressure and the stretching of thearterial wall.

Some aspects of the present subject matter locally stimulate specificnerve endings in arterial walls rather than stimulate afferent nervetrunks in an effort to stimulate a desire response (e.g. reducedhypertension) while reducing the undesired effects of indiscriminatestimulation of the nervous system. For example, some embodimentsstimulate baroreceptor sites in the pulmonary artery. Some embodimentsof the present subject matter involve stimulating either baroreceptorsites or nerve endings in the aorta, the chambers of the heart, and thefat pads of the heart, and some embodiments of the present subjectmatter involve stimulating an afferent nerve trunk, such as the vagus,carotid and aortic nerves. Some embodiments stimulate afferent nervetrunks using a cuff electrode, and some embodiments stimulate afferentnerve trunks using an intravascular lead positioned in a blood vesselproximate to the nerve, such that the electrical stimulation passesthrough the vessel wall to stimulate the afferent nerve trunk.

FIGS. 2A-2C illustrate a heart. As illustrated in FIG. 2A, the heart 201includes a superior vena cava 202, an aortic arch 203, and a pulmonaryartery 204, and is useful to provide a contextual relationship with theillustrations in FIGS. 3-5. As is discussed in more detail below, thepulmonary artery 204 includes baroreceptors. A lead is capable of beingintravascularly inserted through a peripheral vein and through thetricuspid valve into the right ventricle of the heart (not expresslyshown in the figure) similar to a cardiac pacemaker lead, and continuefrom the right ventricle through the pulmonary valve into the pulmonaryartery. A portion of the pulmonary artery and aorta are proximate toeach other. Various embodiments stimulate baroreceptors in the aortausing a lead intravascularly positioned in the pulmonary artery. Thus,according to various aspects of the present subject matter, thebaroreflex is stimulated in or around the pulmonary artery by at leastone electrode intravascularly inserted into the pulmonary artery.Alternatively, a wireless stimulating device, with or without pressuresensing capability, may be positioned via catheter into the pulmonaryartery. Control of stimulation and/or energy for stimulation may besupplied by another implantable or external device via ultrasonic,electromagnetic or a combination thereof. Aspects of the present subjectmatter provide a relatively noninvasive surgical technique to implant abaroreceptor stimulator intravascularly into the pulmonary artery.

FIGS. 2B-2C illustrate the right side and left side of the heart,respectively, and further illustrate cardiac fat pads which have nerveendings that function as baroreceptor sites. FIG. 2B illustrates theright atrium 267, right ventricle 268, sinoatrial node 269, superiorvena cava 202, inferior vena cava 270, aorta 271, right pulmonary veins272, and right pulmonary artery 273. FIG. 2B also illustrates a cardiacfat pad 274 between the superior vena cava and aorta. Baroreceptor nerveendings in the cardiac fat pad 274 are stimulated in some embodimentsusing an electrode screwed into the fat pad, and are stimulated in someembodiments using an intravenously-fed lead proximately positioned tothe fat pad in a vessel such as the right pulmonary artery or superiorvena cava, for example. FIG. 2C illustrates the left atrium 275, leftventricle 276, right atrium 267, right ventricle 268, superior vena cava202, inferior vena cava 270, aorta 271, right pulmonary veins 272, leftpulmonary vein 277, right pulmonary artery 273, and coronary sinus 278.FIG. 2C also illustrates a cardiac fat pad 279 located proximate to theright cardiac veins and a cardiac fat pad 280 located proximate to theinferior vena cava and left atrium. Baroreceptor nerve endings in thefat pad 279 are stimulated in some embodiments using an electrodescrewed into the fat pad 279, and are stimulated in some embodimentsusing an intravenously-fed lead proximately positioned to the fat pad ina vessel such as the right pulmonary artery 273 or right pulmonary vein272, for example. Baroreceptors in the fat pad 280 are stimulated insome embodiments using an electrode screwed into the fat pad, and arestimulated in some embodiments using an intravenously-fed leadproximately positioned to the fat pad in a vessel such as the inferiorvena cava 270 or coronary sinus or a lead in the left atrium 275, forexample.

FIG. 3 illustrates baroreceptors in the area of the carotid sinuses 305,aortic arch 303 and pulmonary artery 304. The aortic arch 303 andpulmonary artery 304 were previously illustrated with respect to theheart in FIG. 2A. As illustrated in FIG. 3, the vagus nerve 306 extendsand provides sensory nerve endings 307 that function as baroreceptors inthe aortic arch 303, in the carotid sinus 305 and in the common carotidartery 310. The glossopharyngeal nerve 308 provides nerve endings 309that function as baroreceptors in the carotid sinus 305. These nerveendings 307 and 309, for example, are sensitive to stretching of thewall resulting from increased pressure from within. Activation of thesenerve endings reduce pressure. Although not illustrated in the figures,the fat pads and the atrial and ventricular chambers of the heart alsoinclude baroreceptors. Cuffs have been placed around afferent nervetrunks, such as the vagal nerve, leading from baroreceptors to vasomotorcenters to stimulate the baroreflex. According to various embodiments ofthe present subject matter, afferent nerve trunks can be stimulatedusing a cuff or intravascularly-fed lead positioned in a blood vesselproximate to the afferent nerves.

FIG. 4 illustrates baroreceptors in and around a pulmonary artery 404.The superior vena cava 402 and the aortic arch 403 are also illustrated.As illustrated, the pulmonary artery 404 includes a number ofbaroreceptors 411, as generally indicated by the dark area. Furthermore,a cluster of closely spaced baroreceptors is situated near theattachment of the ligamentum arteriosum 412. FIG. 4 also illustrates theright ventricle 413 of the heart, and the pulmonary valve 414 separatingthe right ventricle 413 from the pulmonary artery 404. According tovarious embodiments of the present subject matter, a lead is insertedthrough a peripheral vein and threaded through the tricuspid valve intothe right ventricle, and from the right ventricle 413 through thepulmonary valve 414 and into the pulmonary artery 404 to stimulatebaroreceptors in and/or around the pulmonary artery. In variousembodiments, for example, the lead is positioned to stimulate thecluster of baroreceptors near the ligamentum arteriosum 412. FIG. 5illustrates baroreceptor fields 512 in the aortic arch 503, near theligamentum arteriosum and the trunk of the pulmonary artery 504. Someembodiments position the lead in the pulmonary artery to stimulatebaroreceptor sites in the aorta and/or fat pads, such as are illustratedin FIGS. 2B-2C.

FIG. 6 illustrates a known relationship between respiration 615 andblood pressure 616 when the left aortic nerve is stimulated. When thenerve is stimulated at 617, the blood pressure 616 drops, and therespiration 615 becomes faster and deeper, as illustrated by the higherfrequency and amplitude of the respiration waveform. The respiration andblood pressure appear to return to the pre-stimulated state inapproximately one to two minutes after the stimulation is removed.Various embodiments of the present subject matter use this relationshipbetween respiration and blood pressure by using respiration as asurrogate parameter for blood pressure.

FIG. 7 illustrates a known blood pressure response to carotid nervestimulation in a hypertensive dog during 6 months of intermittentcarotid nerve stimulation. The figure illustrates that the bloodpressure of a stimulated dog 718 is significantly less than the bloodpressure of a control dog 719 that also has high blood pressure. Thus,intermittent stimulation is capable of triggering the baroreflex toreduce high blood pressure.

Heart failure refers to a clinical syndrome in which cardiac functioncauses a below normal cardiac output that can fall below a leveladequate to meet the metabolic demand of peripheral tissues. Heartfailure may present itself as congestive heart failure (CHF) due to theaccompanying venous and pulmonary congestion. Heart failure can be dueto a variety of etiologies such as ischemic heart disease.

Heart failure patients have reduced autonomic balance, which isassociated with LV dysfunction and increased mortality. Modulation ofthe sympathetic and parasympathetic nervous systems has potentialclinical benefit in preventing remodeling and death in heart failure andpost-MI patients. Direct electrical stimulation can activate thebaroreflex, inducing a reduction of sympathetic nerve activity andreducing blood pressure by decreasing vascular resistance. Sympatheticinhibition and parasympathetic activation have been associated withreduced arrhythmia vulnerability following a myocardial infarction,presumably by increasing collateral perfusion of the acutely ischemicmyocardium and decreasing myocardial damage.

Following myocardial infarction (MI) or other cause of decreased cardiacoutput, a complex remodeling process of the ventricles occurs thatinvolves structural, biochemical, neurohormonal, and electrophysiologicfactors. Ventricular remodeling is triggered by a physiologicalcompensatory mechanism that acts to increase cardiac output due toso-called backward failure which increases the diastolic fillingpressure of the ventricles and thereby increases the so-called preload(i.e., the degree to which the ventricles are stretched by the volume ofblood in the ventricles at the end of diastole). An increase in preloadcauses an increase in stroke volume during systole, a phenomena known asthe Frank-Starling principle. When the ventricles are stretched due tothe increased preload over a period of time, however, the ventriclesbecome dilated. The enlargement of the ventricular volume causesincreased ventricular wall stress at a given systolic pressure. Alongwith the increased pressure-volume work done by the ventricle, this actsas a stimulus for hypertrophy of the ventricular myocardium. Thedisadvantage of dilatation is the extra workload imposed on normal,residual myocardium and the increase in wall tension (Laplace's Law)which represent the stimulus for hypertrophy. If hypertrophy is notadequate to match increased tension, a vicious cycle ensues which causesfurther and progressive dilatation.

As the heart begins to dilate, afferent baroreceptor and cardiopulmonaryreceptor signals are sent to the vasomotor central nervous systemcontrol center, which responds with hormonal secretion and sympatheticdischarge. It is the combination of hemodynamic, sympathetic nervoussystem and hormonal alterations (such as presence or absence ofangiotensin converting enzyme (ACE) activity) that ultimately accountfor the deleterious alterations in cell structure involved inventricular remodeling. The sustained stresses causing hypertrophyinduce apoptosis (i.e., programmed cell death) of cardiac muscle cellsand eventual wall thinning which causes further deterioration in cardiacfunction. Thus, although ventricular dilation and hypertrophy may atfirst be compensatory and increase cardiac output, the processesultimately result in both systolic and diastolic dysfunction(decompensation). It has been shown that the extent of ventricularremodeling is positively correlated with increased mortality in post-MIand heart failure patients.

Stimulator Systems

Various embodiments of the present subject matter relate to neuralstimulator (NS) (e.g. baroreflex stimulator) devices or components.Neural stimulation can be used to stimulate nerve traffic or inhibitnerve traffic. An example of neural stimulation to stimulate nervetraffic is a lower frequency signal (e.g. within a range on the order of20 Hz to 50 Hz). An example of neural stimulation to inhibit nervetraffic is a higher frequency signal (e.g. within a range on the orderof 120 Hz to 150 Hz. Other methods for stimulating and inhibiting nervetraffic have been proposed, including other embodiments that applyelectrical stimulation pulses to desired neural targets usingstimulation electrodes positioned at predetermined locations.Additionally, other energy types such as ultrasound, light or magneticenergy have been proposed for use in stimulating nerves. According tovarious embodiments of the present subject matter, sympathetic neuraltargets include, but are not limited to, a peroneal nerve, a sympatheticcolumn in a spinal cord, and cardiac post-ganglionic sympatheticneurons. According to various embodiments of the present subject matter,parasympathetic neural targets include, but are not limited to, a vagusnerve, a baroreceptor, and a cardiac fat pad.

Examples of neural stimulators include anti-hypertension (AHT) devicesor AHT components that are used to treat hypertension, neuralstimulators to provide anti-remodeling therapy, and the like. Variousembodiments of the present subject matter include stand-aloneimplantable baroreceptor stimulator systems, include implantable devicesthat have integrated NS and cardiac rhythm management (CRM) components,and include systems with at least one implantable NS device and animplantable CRM device capable of communicating with each other eitherwirelessly or through a wire lead connecting the implantable devices.Integrating NS and CRM functions that are either performed in the sameor separate devices improves aspects of the NS therapy and cardiactherapy by allowing these therapies to work together intelligently.

FIG. 8 illustrates a system 820 including an implantable medical device(IMD) 821 and a programmer 822, according to various embodiments of thepresent subject matter. Various embodiments of the IMD 821 includeneural stimulator functions only, and various embodiments include acombination of NS and CRM functions. Some embodiments of the neuralstimulator provide AHT functions. The programmer 822 and the IMD 821 arecapable of wirelessly communicating data and instructions. In variousembodiments, for example, the programmer 822 and IMD 821 use telemetrycoils to wirelessly communicate data and instructions. Thus, theprogrammer can be used to adjust the programmed therapy provided by theIMD 821, and the IMD can report device data (such as battery and leadresistance) and therapy data (such as sense and stimulation data) to theprogrammer using radio telemetry, for example. According to variousembodiments, the IMD 821 stimulates baroreceptors to provide NS therapysuch as AHT therapy. Various embodiments of the IMD 821 stimulatebaroreceptors in the pulmonary artery using a lead fed through the rightventricle similar to a cardiac pacemaker lead, and further fed into thepulmonary artery. According to various embodiments, the IMD 821 includesa sensor to sense ANS activity. Such a sensor can be used to performfeedback in a closed loop control system. For example, variousembodiments sense surrogate parameters, such as respiration and bloodpressure, indicative of ANS activity. Various embodiments includeactivity sensor(s) such as heart rate, minute ventilation, motionsensors, and the like. According to various embodiments, the IMD furtherincludes cardiac stimulation capabilities, such as pacing anddefibrillating capabilities in addition to the capabilities to stimulatebaroreceptors and/or sense ANS activity.

FIG. 9 illustrates an implantable medical device (IMD) 921 such as theIMD 821 shown in the system 820 of FIG. 8, according to variousembodiments of the present subject matter. The illustrated IMD 921performs NS functions. Some embodiments of the illustrated IMD 921performs an AHT function, and thus illustrates an implantable AHTdevice. The illustrated device 921 includes controller circuitry 923 anda memory 924. The controller circuitry 923 is capable of beingimplemented using hardware, software, and combinations of hardware andsoftware. For example, according to various embodiments, the controllercircuitry 923 includes a processor to perform instructions embedded inthe memory 924 to perform functions associated with NS therapy such asAHT therapy. For example, the illustrated device 921 further includes atransceiver 925 and associated circuitry for use to communicate with aprogrammer or another external or internal device. Various embodimentshave wireless communication capabilities. For example, some transceiverembodiments use a telemetry coil to wirelessly communicate with aprogrammer or another external or internal device.

The illustrated device 921 further includes neural stimulator circuitry926. Various embodiments of the device 921 also includes sensorcircuitry 927. One or more leads are able to be connected to the sensorcircuitry 927 and the stimulator circuitry 926. The neural stimulatorcircuitry 926 is used to apply electrical stimulation pulses to desiredneural targets (e.g. baroreflex sites or other neural targets) throughone or more stimulation electrodes. The sensor circuitry 927 is used todetect and process ANS nerve activity and/or surrogate parameters suchas blood pressure, respiration and the like, to determine the ANSactivity.

According to various embodiments, the stimulator circuitry 926 includesmodules to set any one or any combination of two or more of thefollowing pulse features: the amplitude 928 of the stimulation pulse,the frequency 929 of the stimulation pulse, the burst frequency 930 orduty cycle of the pulse, and the wave morphology 931 of the pulse.Examples of wave morphology include a square wave, triangle wave,sinusoidal wave, and waves with desired harmonic components to mimicwhite noise such as is indicative of naturally-occurring baroreflexstimulation.

FIGS. 10A-10C illustrate a baroreceptor stimulation lead with anintegrated pressure sensor (IPS), according to various embodiments ofthe present subject matter. Although not drawn to scale, theseillustrated leads 1032A, 1032B and 1032C include an IPS 1033 with abaroreceptor stimulator electrode 1034 to monitor changes in bloodpressure, and thus the effect of the baroreceptor stimulation. Theselead illustrations should not be read as limiting other aspects andembodiments of the present subject matter. In various embodiments, forexample, micro-electrical mechanical systems (MEMS) technology is usedto sense the blood pressure. Some sensor embodiments determine bloodpressure based on a displacement of a membrane.

FIGS. 10A-10C illustrate an IPS on a lead. Some embodiments implant anIPS in an IMD or NS device. The stimulator and sensor functions can beintegrated, even if the stimulator and sensors are located in separateleads or positions.

The lead 1032A illustrated in FIG. 10A includes a distally-positionedbaroreceptor stimulator electrode 1034 and an IPS 1033. This lead, forexample, is capable of being intravascularly introduced to stimulate abaroreceptor site, such as the baroreceptor sites in the pulmonaryartery, aortic arch, ligamentum arteriosum, the coronary sinus, in theatrial and ventricular chambers, and/or in cardiac fat pads.

The lead 1032B illustrated in FIG. 10B includes a tip electrode 1035, afirst ring electrode 1036, second ring electrode 1034, and an IPS 1033.This lead may be intravascularly inserted into or proximate to chambersof the heart and further positioned proximate to baroreceptor sites suchthat at least some of the electrodes 1035, 1036 and 1034 are capable ofbeing used to pace or otherwise stimulate the heart, and at least someof the electrodes are capable of stimulating at least one baroreceptorsite. The IPS 1033 is used to sense the blood pressure. In variousembodiments, the IPS is used to sense the blood pressure in the vesselproximate to the baroreceptor site selected for stimulation.

The lead 1032C illustrated in FIG. 10C includes a distally-positionedbaroreceptor stimulator electrode 1034, an IPS 1033 and a ring electrode1036. This lead 1032C may, for example, be intravascularly inserted intothe right atrium and ventricle, and then through the pulmonary valveinto the pulmonary artery. Depending on programming in the device, theelectrode 1036 can be used to pace and/or sense cardiac activity, suchas that which may occur within the right ventricle, and the electrode1034 and IPS 1033 are located near baroreceptors in or near thepulmonary artery to stimulate and sense, either directly or indirectlythrough surrogate parameters, baroreflex activity.

Thus, various embodiments of the present subject matter provide animplantable NS device that automatically modulates baroreceptorstimulation using an IPS. Integrating the pressure sensor into the leadprovides localized feedback for the stimulation. This localized sensingimproves feedback control. For example, the integrated sensor can beused to compensate for inertia of the baroreflex such that the target isnot continuously overshot. According to various embodiments, the devicemonitors pressure parameters such as mean arterial pressure, systolicpressure, diastolic pressure and the like. As mean arterial pressureincreases or remains above a programmable target pressure, for example,the device stimulates baroreceptors at an increased rate to reduce bloodpressure and control hypertension. As mean arterial pressure decreasestowards the target pressure, the device responds by reducingbaroreceptor stimulation. In various embodiments, the algorithm takesinto account the current metabolic state (cardiac demand) and adjustsneural stimulation accordingly. A NS device having an IPS is able toautomatically modulate baroreceptor stimulation, which allows animplantable NS device to determine the level of hypertension in thepatient and respond by delivering the appropriate level of therapy.However, it is noted that other sensors, including sensors that do notreside in an NS or neural stimulator device, can be used to provideclose loop feedback control.

FIG. 11 illustrates an implantable medical device (IMD) 1121 such asshown at 821 in FIG. 8 having a neural stimulation (NS) component 1137and cardiac rhythm management (CRM) component 1138, according to variousembodiments of the present subject matter. The illustrated device 1121includes a controller 1123 and a memory 1124. According to variousembodiments, the controller 1123 includes hardware, software, or acombination of hardware and software to perform the baroreceptorstimulation and CRM functions. For example, the programmed therapyapplications discussed in this disclosure are capable of being stored ascomputer-readable instructions embodied in memory and executed by aprocessor. According to various embodiments, the controller 1123includes a processor to execute instructions embedded in memory toperform the baroreceptor stimulation and CRM functions. The illustrateddevice 1121 further includes a transceiver 1125 and associated circuitryfor use to communicate with a programmer or another external or internaldevice. Various embodiments include a telemetry coil.

The CRM therapy section 1138 includes components, under the control ofthe controller, to stimulate a heart and/or sense cardiac signals usingone or more electrodes. The CRM therapy section includes a pulsegenerator 1139 for use to provide an electrical signal through anelectrode to stimulate a heart, and further includes sense circuitry1140 to detect and process sensed cardiac signals. An interface 1141 isgenerally illustrated for use to communicate between the controller 1123and the pulse generator 1139 and sense circuitry 1140. Three electrodesare illustrated as an example for use to provide CRM therapy. However,the present subject matter is not limited to a particular number ofelectrode sites. Each electrode may include its own pulse generator andsense circuitry. However, the present subject matter is not so limited.The pulse generating and sensing functions can be multiplexed tofunction with multiple electrodes.

The NS therapy section 1137 includes components, under the control ofthe controller, to stimulate a baroreceptor and/or sense ANS parametersassociated with nerve activity or surrogates of ANS parameters such asblood pressure and respiration. Three interfaces 1142 are illustratedfor use to provide ANS therapy. However, the present subject matter isnot limited to a particular number interfaces, or to any particularstimulating or sensing functions. Pulse generators 1143 are used toprovide electrical pulses to an electrode for use to stimulate abaroreceptor site. According to various embodiments, the pulse generatorincludes circuitry to set, and in some embodiments change, the amplitudeof the stimulation pulse, the frequency of the stimulation pulse, theburst frequency of the pulse, and the morphology of the pulse such as asquare wave, triangle wave, sinusoidal wave, and waves with desiredharmonic components to mimic white noise or other signals. Sensecircuits 1144 are used to detect and process signals from a sensor, suchas a sensor of nerve activity, blood pressure, respiration, and thelike. The interfaces 1142 are generally illustrated for use tocommunicate between the controller 1123 and the pulse generator 1143 andsense circuitry 1144. Each interface, for example, may be used tocontrol a separate lead. Various embodiments of the NS therapy sectiononly include a pulse generator to stimulate baroreceptors. For example,the NS therapy section provides AHT therapy.

An aspect of the present subject matter relates to achronically-implanted stimulation system specially designed to treathypertension by monitoring blood pressure and stimulating baroreceptorsto activate the baroreceptor reflex and inhibit sympathetic dischargefrom the vasomotor center. Baroreceptors are located in variousanatomical locations such as the carotid sinus and the aortic arch.Other baroreceptor locations include the pulmonary artery, including theligamentum arteriosum, and sites in the atrial and ventricular chambers.In various embodiments, the system is integrated into apacemaker/defibrillator or other electrical stimulator system.Components of the system include a high-frequency pulse generator,sensors to monitor blood pressure or other pertinent physiologicalparameters, leads to apply electrical stimulation to baroreceptors,algorithms to determine the appropriate time to administer stimulation,and algorithms to manipulate data for display and patient management.

Various embodiments relate to a system that seeks to deliverelectrically mediated NS therapy, such as AHT therapy, to patients.Various embodiments combine a “stand-alone” pulse generator with aminimally invasive, unipolar lead that directly stimulates baroreceptorsin the vicinity of the heart, such as in the pulmonary artery. Thisembodiment is such that general medical practitioners lacking the skillsof specialist can implant it. Various embodiments incorporate a simpleimplanted system that can sense parameters indicative of blood pressure.This system adjusts the therapeutic output (waveform amplitude,frequency, etc.) so as to maintain a desired quality of life. In variousembodiments, an implanted system includes a pulse generating device andlead system, the stimulating electrode of which is positioned nearendocardial baroreceptor tissues using transvenous implant technique(s).Another embodiment includes a system that combines NS therapy withtraditional bradyarrhythmia, tachyarrhythmia, and/or congestive heartfailure (CHF) therapies. Some embodiments use an additional“baroreceptor lead” that emerges from the device header and is pacedfrom a modified traditional pulse generating system. In anotherembodiment, a traditional CRM lead is modified to incorporate proximalelectrodes that are naturally positioned near baroreceptor sites. Withthese leads, distal electrodes provide CRM therapy and proximateelectrodes stimulate baroreceptors.

A system according to these embodiments can be used to augment partiallysuccessful treatment strategies. As an example, undesired side effectsmay limit the use of some pharmaceutical agents. The combination of asystem according to these embodiments with reduced drug doses may beparticularly beneficial.

According to various embodiments, the lead(s) and the electrode(s) onthe leads are physically arranged with respect to the heart in a fashionthat enables the electrodes to properly transmit pulses and sensesignals from the heart, and with respect to baroreceptors to stimulatethe baroreflex. As there may be a number of leads and a number ofelectrodes per lead, the configuration can be programmed to use aparticular electrode or electrodes. According to various embodiments,the baroreflex is stimulated by stimulating afferent nerve trunks.

FIG. 12 illustrates a system 1220 including a programmer 1222, animplantable neural stimulator (NS) device 1237 and an implantablecardiac rhythm management (CRM) device 1238, according to variousembodiments of the present subject matter. Various aspects involve amethod for communicating between an NS device 1237, such as an AHTdevice, and a CRM device 1238 or other cardiac stimulator. In variousembodiments, this communication allows one of the devices 1237 or 1238to deliver more appropriate therapy (i.e. more appropriate NS therapy orCRM therapy) based on data received from the other device. Someembodiments provide on-demand communications. In various embodiments,this communication allows each of the devices 1237 and 1238 to delivermore appropriate therapy (i.e. more appropriate NS therapy and CRMtherapy) based on data received from the other device. The illustratedNS device 1237 and the CRM device 1238 are capable of wirelesslycommunicating with each other, and the programmer is capable ofwirelessly communicating with at least one of the NS and the CRM devices1237 and 1238. For example, various embodiments use telemetry coils towirelessly communicate data and instructions to each other. In otherembodiments, communication of data and/or energy is by ultrasonic means.

In some embodiments, the NS device 1237 stimulates the baroreflex toprovide NS therapy, and senses ANS activity directly or using surrogateparameters, such as respiration and blood pressure, indicative of ANSactivity. The CRM device 1238 includes cardiac stimulation capabilities,such as pacing and defibrillating capabilities. Rather than providingwireless communication between the NS and CRM devices 1237 and 1238,various embodiments provide a communication cable or wire, such as anintravenously-fed lead, for use to communicate between the NS device1237 and the CRM device 1238.

FIG. 13 illustrates an implantable neural stimulator (NS) device 1337such as shown at 1237 in the system of FIG. 12, according to variousembodiments of the present subject matter. FIG. 14 illustrates animplantable cardiac rhythm management (CRM) device 1438 such as shown at1238 in the system of FIG. 12, according to various embodiments of thepresent subject matter. Functions of the components for the NS device1337 were previously discussed with respect to FIGS. 9 and 11 (the NScomponent 1137), and functions of the components for the CRM device 1238were previously discussed with respect to FIG. 11 (the CRM component1138). In the interest of brevity, these discussions with respect to theNS and CRM functions are not repeated here. Various embodiments of theNS and CRM devices include wireless transceivers 1325 and 1425,respectively, to wirelessly communicate with each other. Variousembodiments of the NS and CRM devices include a telemetry coil orultrasonic transducer to wirelessly communicate with each other.

According to various embodiments, for example, the NS device is equippedwith a telemetry coil, allowing data to be exchanged between it and theCRM device, allowing the NS device to modify therapy based onelectrophysiological parameters such as heart rate, minute ventilation,atrial activation, ventricular activation, and cardiac events. Inaddition, the CRM device modifies therapy based on data received fromthe NS device, such as mean arterial pressure, systolic and diastolicpressure, and baroreceptors stimulation rate.

Some NS device embodiments are able to be implanted in patients withexisting CRM devices, such that the functionality of the NS device isenhanced by receiving physiological data that is acquired by the CRMdevice. The functionality of two or more implanted devices is enhancedby providing communication capabilities between or among the implanteddevices. In various embodiments, the functionality is further enhancedby designing the devices to wirelessly communicate with each other.

FIG. 15 illustrates a programmer 1522, such as the programmer 822 and1222 illustrated in the systems of FIGS. 8 and 12, or other externaldevice to communicate with the implantable medical device(s) 1237 and/or1238, according to various embodiments of the present subject matter. Anexample of another external device includes Personal Digital Assistants(PDAs) or personal laptop and desktop computers in an Advanced PatientManagement (APM) system. The illustrated device 1522 includes controllercircuitry 1545 and a memory 1546. The controller circuitry 1545 iscapable of being implemented using hardware, software, and combinationsof hardware and software. For example, according to various embodiments,the controller circuitry 1545 includes a processor to performinstructions embedded in the memory 1546 to perform a number offunctions, including communicating data and/or programming instructionsto the implantable devices. The illustrated device 1522 further includesa transceiver 1547 and associated circuitry for use to communicate withan implantable device. Various embodiments have wireless communicationcapabilities. For example, various embodiments of the transceiver 1547and associated circuitry include a telemetry coil for use to wirelesslycommunicate with an implantable device. The illustrated device 1522further includes a display 1548, input/output (I/O) devices 1549 such asa keyboard or mouse/pointer, and a communications interface 1550 for useto communicate with other devices, such as over a communication network.

Programmed Therapy Applications

NS and/or CRM functions of a system, whether implemented in two separateand distinct implantable devices or integrated as components into oneimplantable device, includes processes for performing NS and/or CRMtherapy or portions of the therapy. In some embodiments, the NS therapyprovides AHT therapy. In some embodiments, the neural stimulationtherapy prevents and/or treats ventricular remodeling.

Activity of the autonomic nervous system is at least partly responsiblefor the ventricular remodeling which occurs as a consequence of an MI ordue to heart failure. It has been demonstrated that remodeling can beaffected by pharmacological intervention with the use of, for example,ACE inhibitors and beta-blockers. Pharmacological treatment carries withit the risk of side effects, however, and it is also difficult tomodulate the effects of drugs in a precise manner. Another issue withdrug therapy is patient non-compliance. Embodiments of the presentsubject matter employ electrostimulatory means to modulate autonomicactivity, referred to as anti-remodeling therapy or ART. When deliveredin conjunction with ventricular resynchronization pacing, also referredto as remodeling control therapy (RCT), such modulation of autonomicactivity acts synergistically to reverse or prevent cardiac remodeling.

Increased sympathetic nervous system activity following ischemia oftenresults in increased exposure of the myocardium to epinephrine andnorepinephrine. These catecholamines activate intracellular pathwayswithin the myocytes, which lead to myocardial death and fibrosis.Stimulation of the parasympathetic nerves (vagus) inhibits this effect.According to various embodiments, the present subject matter selectivelyactivates the vagal cardiac nerves in addition to CRT in heart failurepatients to protect the myocardium from further remodeling andarrhythmogenesis. Other potential benefits of stimulating vagal cardiacnerves in addition to CRT include reducing inflammatory responsefollowing myocardial infarction, and reducing the electrical stimulationthreshold for defibrillating. For example, when a ventriculartachycardia is sensed, vagal nerve stimulation is applied, and then adefibrillation shock is applied. The vagal nerve stimulation allows thedefibrillation shock to be applied at less energy. Also, parasympatheticstimulation may terminate an arrhythmia or otherwise increase theeffectiveness of an anti-arrhythmia treatment.

Processes can be performed by a processor executing computer-readableinstructions embedded in memory, for example. Therapies include a numberof applications, which have various processes and functions, some ofwhich are identified and discussed below. The processes and functions ofthese therapies are not necessarily mutually exclusive, as someembodiments of the present subject matter include combinations of two ormore of the below-identified processes and functions.

Accounting for Neural Stimulation to Accurately Sense Signals

FIGS. 16A-16D illustrate a system and methods to prevent interferencebetween electrical stimulation from an neural stimulator (NS) device andsensing by a cardiac rhythm management (CRM) device, according tovarious embodiments of the present subject matter. Neural stimulation isaccounted for to improve the ability to sense signals, and thus reduceor eliminate false positives associated with detecting a cardiac event.The NS device includes an AHT device in some embodiments. For example,the NS device communicates with and prevents or otherwise compensatesfor baroreflex stimulation such that the CRM device does notunintentionally react to the baroreflex stimulation, according to someembodiments. Some embodiments automatically synchronize the baroreflexstimulation with an appropriate refraction in the heart. For example,some systems automatically synchronize stimulation of baroreceptors inor around the pulmonary artery with atrial activation. Thus, thefunctions of the CRM device are not adversely affected by detectingfar-field noise generated by the baroreflex stimulation, even when thebaroreflex stimulations are generated near the heart and the CRM sensorsthat detect the cardiac electrical activation.

FIG. 16A generally illustrates a system 1654 that includes NS functions1651 (such as may be performed by a NS device or a NS component in anintegrated NS/CRM device), CRM functions 1652 (such as may be performedby a CRM device or a CRM component in an integrated NS/CRM device) andcapabilities to communicate 1653 between the NS and CRM functions. Theillustrated communication is bidirectional wireless communication.However, the present subject matter also contemplates unidirectionalcommunication, and further contemplates wired communication.Additionally, the present subject matter contemplates that the NS andCRM functions 1651 and 1652 can be integrated into a single implantabledevice such that the communication signal is sent and received in thedevice, or in separate implantable devices. Although baroreflexstimulation as part of neural stimulation is specifically discussed,this aspect of the present subject matter is also applicable to prevent,or account or otherwise compensate for, unintentional interferencedetectable by a sensor and generated from other electrical stimulators.

FIG. 16B illustrates a process where CRM functions do notunintentionally react to baroreflex stimulation, according to variousembodiments. FIG. 16B illustrates a process where the NS device orcomponent 1651 sends an alert or otherwise informs the CRM device orcomponent when baroreceptors are being electrically stimulated. In theillustrated embodiment, the NS device/component determines at 1655 ifelectrical stimulation, such as baroreflex stimulation, is to beapplied. When electrical stimulation is to be applied, the NS device orcomponent 1651 sends at 1656 an alert 1657 or otherwise informs the CRMdevice or component 1652 of the electrical stimulation. At 1658, theelectrical stimulation is applied by the NS device/component. At 1659CRM therapy, including sensing, is performed. At 1660, the CRMdevice/component determines whether an alert 1657 has been received fromthe NS device/component. If an alert has been received, an eventdetection algorithm is modified at 1661 to raise a detection threshold,provide a blackout or blanking window, or otherwise prevent theelectrical stimulation in the NS device or component from beingmisinterpreted as an event by the CRM device/component.

FIG. 16C illustrates a process where CRM functions do notunintentionally react to baroreflex stimulation, according to variousembodiments. The CRM device/component 1652 determines a refractoryperiod for the heart at 1662. At 1663, if a refractory period isoccurring or is expected to occur in a predictable amount of time, anenable 1664 corresponding to the refractory is provided to the NSdevice/component 1651. The AHT device/component 1651 determines ifelectrical stimulation is desired at 1655. When desired, the AHTdevice/component applies electrical stimulation during a refractoryperiod at 1666, as controlled by the enable signal 1664. FIG. 16Dillustrates a refractory period at 1667 in a heart and a baroreflexstimulation 1668, and further illustrates that baroreflex stimulation isapplied during the refractory period.

A refractory period includes both absolute and relative refractoryperiods. Cardiac tissue is not capable of being stimulated during theabsolute refractory period. The required stimulation threshold during anabsolute refractory period is basically infinite. The relativerefractory period occurs after the absolute refractory period. Duringthe relative refractory period, as the cardiac tissue begins torepolarize, the stimulation threshold is initially very high and dropsto a normal stimulation threshold by the end of the relative refractoryperiod. Thus, according to various embodiments, a neural stimulatorapplies neural stimulation during either the absolute refractory periodor during a portion of the relative refractory period corresponding asufficiently high stimulation threshold to prevent the neuralstimulation from capturing cardiac tissue.

Various embodiments of the present subject matter relate to a method ofsensing atrial activation and confining pulmonary artery stimulation tothe atrial refractory period, preventing unintentional stimulation ofnearby atrial tissue. An implantable baroreceptor stimulation devicemonitors atrial activation with an atrial sensing lead. A lead in thepulmonary artery stimulates baroreceptors in the vessel wall. However,instead of stimulating these baroreceptors continuously, the stimulationof baroreceptors in the pulmonary artery occurs during the atrialrefractory period to avoid capturing nearby atrial myocardium,maintaining the intrinsic atrial rate and activation. Variousembodiments of the present subject matter combine an implantable devicefor stimulating baroreceptors in the wall of the pulmonary artery withthe capability for atrial sensing. Various embodiments stimulatebaroreceptors in the cardiac fat pads, in the heart chambers, and/orafferent nerves.

FIG. 17 illustrates a system to modulate neural stimulation (e.g.baroreflex stimulation), according to various embodiments of the presentsubject matter. The illustrated system includes a neural stimulator1751, such as stimulator to stimulate baroreceptors in and around thepulmonary artery. The stimulator can be included in a stand-alone NSdevice or as a NS component in an integrated NS/CRM device, for example.The illustrated stimulator 1751 includes a modulator 1769 for use toselectively increase and decrease the applied neural stimulation.According to various embodiments, the modulator 1769 includes any one ofthe following modules: a module 1770 to change the amplitude of thestimulation pulse; a module 1771 to change the frequency of thestimulation pulse; and a module 1772 to change the burst frequency ofthe stimulation pulse.

According to various embodiments, the stimulation circuitry is adaptedto set or adjust any one or any combination of stimulation features.Examples of stimulation features include the amplitude, frequency,polarity and wave morphology of the stimulation signal. Examples of wavemorphology include a square wave, triangle wave, sinusoidal wave, andwaves with desired harmonic components to mimic white noise such as isindicative of naturally-occurring baroreflex stimulation. Someembodiments of the neural stimulation circuitry are adapted to generatea stimulation signal with a predetermined amplitude, morphology, pulsewidth and polarity, and are further adapted to respond to a controlsignal to modify at least one of the amplitude, wave morphology, pulsewidth and polarity. Some embodiments of the neural stimulation circuitryare adapted to generate a stimulation signal with a predeterminedfrequency, and are further adapted to respond to a control signal fromthe controller to modify the frequency of the stimulation signal.

The neural stimulation delivered by the stimulation circuitry can beprogrammed using stimulation instructions, such as a stimulationschedule, stored in a memory. Neural stimulation can be delivered in astimulation burst, which is a train of stimulation pulses at apredetermined frequency. Stimulation bursts can be characterized byburst durations and burst intervals. A burst duration is the length oftime that a burst lasts. A burst interval can be identified by the timebetween the start of successive bursts. A programmed pattern of burstscan include any combination of burst durations and burst intervals. Asimple burst pattern with one burst duration and burst interval cancontinue periodically for a programmed period or can follow a morecomplicated schedule. The programmed pattern of bursts can be morecomplicated, composed of multiple burst durations and burst intervalsequences. The programmed pattern of bursts can be characterized by aduty cycle, which refers to a repeating cycle of neural stimulation ONfor a fixed time and neural stimulation OFF for a fixed time. Duty cycleis specified by the ON time and the cycle time, and thus can have unitsof ON time/cycle time. For example, if the ON/OFF cycle repeats every 1minute and the ON time of the duty cycle is 10 seconds, then the dutycycle is 10 seconds per minute. If the ON/OFF cycle repeats every onehour and the ON time is 5 minutes, then the duty cycle is 5 minutes perhour. According to some embodiments, the neural stimulation iscontrolled by initiating each pulse of the stimulation signal. In someembodiments, the controller circuitry initiates a stimulation signalpulse train, where the stimulation signal responds to a command from thecontroller circuitry by generating a train of pulses at a predeterminedfrequency and burst duration. The predetermined frequency and burstduration of the pulse train can be programmable. The pattern of pulsesin the pulse train can be a simple burst pattern with one burst durationand burst interval or can follow a more complicated burst pattern withmultiple burst durations and burst intervals. In some embodiments, theinitiation and termination of neural stimulation sessions is controlled.The burst duration of the neural stimulation session can beprogrammable. A neural stimulation session may be terminated in responseto an interrupt signal, such as may be generated by one or more sensedparameters or any other condition where it is determined to be desirableto stop neural stimulation.

Various embodiments of the system include any one or any combination ofa physiologic activity monitor 1773, an adverse event detector 1774, arespiration monitor 1775, and a circadian rhythm template 1776 which arecapable of controlling the modulator 1769 of the stimulator 1751 toappropriately apply a desired level of neural stimulation. Each of these1773, 1774, 1775, and 1776 are associated with a method to modulate aneural stimulation signal. According to various embodiments, the systemincludes means to modulate a neural stimulation signal based on thefollowing parameters or parameter combinations: physiologic activity(1773); an adverse event (1774); respiration (1775); circadian rhythm(1776); physiologic activity (1773) and an adverse event (1774);physiologic activity (1773) and respiration (1775); physiologic activity(1773) and circadian rhythm (1776); an adverse event (1774) andrespiration (1775); an adverse event (1774) and circadian rhythm (1776);respiration (1775) and circadian rhythm (1776); physiologic activity(1773), an adverse event (1774), and respiration (1775); physiologicactivity (1773), an adverse event (1774), and circadian rhythm (1776);physiologic activity (1773), respiration (1775), and circadian rhythm(1776); an adverse event (1774), respiration (1775) and circadian rhythm(1776); and physiologic activity (1773), an adverse event (1774),respiration (1775) and circadian rhythm (1776).

The stimulation can be applied to a variety of neural targets. Forexample, the stimulation can be applied to an afferent nerve trunk suchas the vagal nerve using a cuff electrode or an intravascularly-fed leadpositioned proximate to the nerve trunk. The stimulation can be appliedto baroreflex targets such as are located in the pulmonary artery,aortic arch, and carotid sinus, for example, using intravenously-fedleads. The stimulation can be applied to ANS sites located in cardiacfat pads using intravenously-fed leads or by screwing electrodes intothe fat pads. Embodiments of the physiologic activity detector 1773, forexample, include any one or any combination of a heart rate monitor1777A, a minute ventilation monitor 1777B, a motion monitor 1777C, astroke volume monitor 1777D, a respiration rate monitor 1777E, a tidalvolume monitor 1777F, a nerve activity monitor 1777G such as a sensor ofsympathetic activity, a blood pressure monitor 1777H, and a cardiacoutput monitor 17771. The cardiac output monitor can be determined usingheart rate and stroke volume (e.g. cardiac output equals the product ofheart rate and stroke volume). Examples of motion monitors includesensors to detect acceleration such as an accelerometer or piezoelectriccrystal. Other motion sensors may be used, such as motion sensors thatuse electromyography (EMG) sensors to detect muscle movement (e.g. legmovement), and sensors that use global positioning system (GPS)technology to detect movement. GPS technology can include appropriatealgorithms to account for automotive movement (e.g. travel in anautomobile, airplanes, boats and trains). Embodiments of the respirationmonitor 1775 include any one or any combination of a tidal volumemonitor 1780 and a minute ventilation module 1781. Transthoracicimpedance, for example, can be used to determine minute ventilation, andcardiac impedance and ECGs, for example, can be used to determine heartrate. Embodiments of the circadian rhythm template 1776 include any oneor combination of a custom generated template 1782 and a preprogrammedtemplate 1783. These embodiments are discussed in more detail below withrespect to FIGS. 18A-18C, 19A-19B, 20A-20B, 21A-21E, 22 and 23A-23C. Thecircadian rhythm template can be used to provide various neuralstimulation therapies, such as AHT therapy, apnea therapy, postmyocardial infarction therapy, heart failure therapy, and othertherapies.

Modulation of Neural Stimulation (e.g. Baroreflex Stimulation) Based onSystolic Intervals

Activation of the sympathetic or parasympathetic nervous systems isknown to alter certain systolic intervals, primarily the pre-ejectionperiod (PEP), the time interval between sensed electrical activitywithin the ventricle (e.g. sensing of the “R” wave) and the onset ofventricular ejection of blood. The PEP may be measured from the sensedelectrical event to the beginning of pressure increase in the pulmonaryartery, using a pulmonary arterial pressure sensor, or may be measuredto the beginning of an increase in intracardiac impedance, accompanyinga decrease in ventricular volume during ejection, using electrodespositioned in the right or spanning the left ventricle. At rest, asdetermined by heart rate or body activity measured with an accelerometerfor example, neural stimulation is modulated to maintain PEP in apre-programmed range. A sudden decrease in PEP indicates an increase insympathetic tone associated with exercise or emotional stress. Thiscondition may be used to decrease neural stimulation permittingincreases in heart rate and contractility necessary to meet metabolicdemand. In like manner, a subsequent dramatic lengthening of PEP marksthe end of increased metabolic demand. At this time control of bloodpressure with neural stimulation could recommence.

Modulation of Neural Stimulation (e.g. Baroreflex Stimulation) Based onActivity

The present subject matter describes a method of automaticallymodulating neural stimulation (e.g. baroreflex stimulation) based onactivity, such as can be determined by the heart rate, minuteventilation, acceleration and combinations thereof. For example, thefunctionality of a device for electrically stimulating baroreceptors isenhanced by applying at least a relatively high baropacing rate duringrest when metabolic demand is relatively low, and progressively lessbaropacing during physical exertion as metabolic demand increases.Indices of activity are used to automatically modulate the electricalstimulation of baroreceptors, allowing an implantable neural stimulationdevice (e.g. anti-hypertension device) to respond to changes inmetabolic demand. According to various embodiments, a CRM device, suchas a pacemaker, AICD or CRT devices, also has a neural stimulation lead.The device monitors activity through existing methods using, forexample, a blended sensor. A blended sensor includes two sensors tomeasure parameters such as acceleration and minute ventilation. Theoutput of the blended sensor represents a composite parameter. Variousneural stimulation therapies such as AHT therapies, anti-remodelingtherapies, and the like use composite parameters derived from two ormore sensed parameters as discussed within this disclosure. At rest(lower activity) the device delivers neural stimulation at a higherrate, reducing blood pressure and controlling hypertension. As activityincreases, the device responds by temporarily reducing or stoppingneural stimulation. This results in a temporary increase in bloodpressure and cardiac output, allowing the body to respond to increasedmetabolic demand. For example, some embodiments provide baroreflexstimulation during rest and withdraw baroreflex stimulation duringexercise to match normal blood pressure response to exercise. A pressuretransducer can be used to determine activity. Furthermore, activity canbe sensed using sensors that are or have been used to drive rateadaptive pacing. Examples of such sensors include sensor to detect bodymovement, heart rate, QT interval, respiration rate, transthoracicimpedance, tidal volume, minute ventilation, body posture,electroencephalogram (EEG), electrocardiogram (ECG) includingsubcutaneous ECG, electrooculogram (EOG), electromyogram (EMG), muscletone, body temperature, pulse oximetry, time of day and pre-ejectioninterval from intracardiac impedance.

Various embodiments of the cardiac activity monitor includes a sensor todetect at least one pressure parameter such as a mean arterialparameter, a pulse pressure determined by the difference between thesystolic and diastolic pressures, end systolic pressure (pressure at theend of the systole), and end diastolic pressure (pressure at the end ofthe diastole). Various embodiments of the cardiac activity monitorinclude a stroke volume monitor. Heart rate and pressure can be used toderive stroke volume. Various embodiments of the cardiac activitymonitor use at least one electrogram measurement to determine cardiacactivity. Examples of such electrogram measurements include the R-Rinterval, the P-R interval, and the QT interval. Various embodiments ofthe cardiac activity monitor use at least one electrocardiogram (ECG)measurement to determine cardiac activity.

FIGS. 18A-18E illustrate methods for modulating neural stimulation (e.g.baroreflex stimulation) based on a cardiac activity parameter, accordingto various embodiments of the present subject matter. The cardiacactivity can be determined by a CRM device, an NS device, or animplantable device with NS/CRM capabilities. A first process 1884A formodulating neural stimulation (e.g. baroreflex stimulation) based oncardiac activity is illustrated in FIG. 18A. At 1885A the activity levelis determined. According to various embodiments, the determination ofactivity level is based on heart rate, minute ventilation, motion (e.g.acceleration) or any combination of heart rate, minute ventilation, andmotion. In the illustrated process, the activity level has two definedlevels (e.g. HI and LO). In some embodiments, the LO level includes noactivity. It is determined whether the activity level is HI or LO. At1886A, the stimulation level is set based on the determined activitylevel. For example, a LO stimulation level is set if the activity levelis determined to be HI, and a HI stimulation level is set if theactivity level is determined to be LO.

A second process 1884B for modulating neural stimulation (e.g.baroreflex stimulation) based on cardiac activity is illustrated in FIG.18B. At 1885B the activity level is determined. According to variousembodiments, the determination of activity level is based on heart rate,minute ventilation, motion (e.g. acceleration) or any combination ofheart rate, minute ventilation, and motion. In the illustrated process,the activity level has more than two defined levels or n defined levels.The labels assigned to the illustrated n levels includes level 1 for thelowest activity level, level 2 for the second to the lowest activitylevel, level 3 for the third to the lowest activity level, and so on.Level n corresponds to the highest activity level. It is determinedwhether the activity level is level 1, level 2 . . . or level n. At1886B, the neural stimulation level is set based on the determinedactivity level. Available stimulation levels include n levels, wherelevel 1 corresponds to the lowest stimulation level, level 2 correspondsto the second lowest stimulation level, level 3 corresponds to the thirdlowest stimulation level, and so on. Level n corresponds to the higheststimulation level. According to various embodiments, the selected neuralstimulation level is inversely related to the determined activity level.For example, if it is determined that the activity level is at thehighest level (level n), then the stimulation level is set to the lowestlevel (level 1). If it is determined that the activity level is at thesecond highest level (level n-1), then the stimulation level is set tothe second lowest level (level 2). If it is determined that the activitylevel is at the second lowest level (level 2), then the stimulationlevel is set to the second highest level (level n-1). If it isdetermined that the activity level is at the lowest level (level 1),then the stimulation level is set to the highest stimulation level(level n). This embodiment functionally maps the activity levels tostimulation levels; that is, maps the activity to the neural stimulationintensity.

Another process 1884C for modulating neural stimulation (e.g. baroreflexstimulation) based on activity is illustrated in FIG. 18C. In theillustrated process, at least one sensed or acquired activity parameteris compared to at least one reference parameter, and the neuralstimulation intensity is modulated based on results of the comparison.At 1887, an acquired activity parameter is compared to a target activityparameter. The neural stimulation intensity is modulated based on theresults of the comparison. For example, if the acquired activity islower than a reference activity parameter, neural stimulation isincreased at 1888. If the acquired activity is higher than the referenceactivity parameter, neural stimulation is decreased at 1889. If theacquired activity is equal or approximately equal to the referenceactivity parameter, no adjustments are made to the neural stimulationintensity. Various embodiments determine a difference between the sensedor acquired activity and the reference, and adjust the neuralstimulation intensity based on the difference. According to someembodiments, the adjustment of the neural stimulation intensity isproportional to the difference between the sensed or acquired activityand the reference. For example, if the difference is x, the neuralstimulation intensity is either increased (directly proportional) ordecreased (inversely proportional) as a function of x (e.g.intensity=f(x)), where x is the difference between the sensed activityand the reference. The function mapping an activity difference x intoneural stimulation intensity may be implemented as a linear function oras a non-linear function. Additionally, the function can be calculatedfrom a mathematical formula or implemented as a lookup table. If thedifference is 2x, the neural stimulation intensity is either increasedor decreased as a function of x (e.g. intensity=f(2x)). If thedifference is ½(x), the neural stimulation intensity is either increasedor decreased as a function of x (e.g. intensity=f(0.5x)). The activityreference level can be adjusted dynamically. By way of example and notlimitation, the activity reference level can be calculated as theaverage activity over a period of time (e.g. 5 to 60 minutes). Thedynamic adjustment of the reference level allows the neural stimulationlevel to be adjusted proportional to a transient change in averageactivity level compared to some retrospective period.

An embodiment of a process 1884D for modulating neural stimulation basedon activity is illustrated in FIG. 18D. As illustrated at 1801, it isdetermined whether a detected or monitored activity is above athreshold. According to various embodiments, the determination ofactivity level is based on heart rate, minute ventilation, accelerationor any combination of heart rate, minute ventilation, acceleration.Pressure sensors can be used to determine activity. According to variousembodiments, sensors that can be used to drive rate adapted pacing canbe used to determine activity. Examples of such sensors have beenpreviously provided in this document. If the activity is above athreshold, the neural stimulation is not applied at 1802; and if theactivity is not above the threshold, the neural stimulation is appliedat 1803. Since the neural stimulation is only applied in this embodimentif the activity is not above a predetermined threshold, the activitydetermination can thus function as an enable for a neural stimulationtherapy.

An embodiment of a process 1884E for modulating neural stimulation basedon activity is illustrated in FIG. 18E. The sensed activity isassociated with a physiologic response. For example, it is appropriatefor heart rate to increase during periods of exercise. As illustrated,neural stimulation is applied at 1804. The neural stimulation can bepart of a therapy such as an anti-hypertension (AHT) or anti-remodelingtherapy. If the activity is above a predetermined threshold asdetermined at 1805, neural stimulation parameters(s) are adjusted at1806 to values to abate (reduce or avoid) effects of the neuralstimulation on the physiologic response associated with the sensedactivity. Thus, for example, the process allows an appropriatephysiologic response to exercise.

An aspect of the present subject matter relates to a method ofautomatically modulating the intensity of baroreceptor stimulation basedon respiration, as determined by tidal volume or minute ventilation.Instead of applying continuous baroreceptor stimulation, the NS devicemonitors the level of hypertension and delivers an appropriate level oftherapy, using respiration as a surrogate for blood pressure, allowingthe device to modulate the level of therapy. The present subject matteruses indices of respiration, such as impedance, to determined tidalvolume and minute ventilation and to automatically modulate baroreceptorstimulation. Thus, an implantable NS device is capable of determiningthe level of hypertension in the patient and respond by delivering anappropriate level of therapy. In various embodiments, an implantable NSdevice contains a sensor to measure tidal volume or minute ventilation.For example, various embodiments measure transthoracic impedance toobtain a rate of respiration. The device receives this data from a CRMdevice in some embodiments. The NS device periodically monitors theserespiration parameters. As respiration decreases or remains below aprogrammable target, the device stimulates baroreceptors at an increasedrate, reducing blood pressure and controlling hypertension. As meanarterial pressure increases towards the target, the device responds byreducing baroreceptor stimulation. In this way, the AHT devicecontinuously delivers an appropriate level of therapy.

FIGS. 19A-19B illustrate methods for modulating baroreceptor stimulationbased on a respiration parameter, according to various embodiments ofthe present subject matter. The respiration parameter can be determinedby a CRM device, an NS device, or an implantable device with NS/CRMcapabilities. One embodiment of a method for modulating baroreceptorstimulation based on a respiration parameter is illustrated at 1910A inFIG. 19A. The respiration level is determined at 1911, and thebaroreceptor stimulation level is set at 1912 based on the determinedrespiration level. According to various embodiments, the desiredbaropacing level is tuned at 1913. For example, one embodiment comparesan acquired parameter to a target parameter at 1914. The baropacing canbe increased at 1915 or decreased at 1916 based on the comparison of theacquired parameter to the target parameter.

One embodiment of a method for modulating baroreceptor stimulation basedon a respiration parameter is illustrated at 1910B in FIG. 19B. At 1916,a baroreflex event trigger occurs, which triggers an algorithm for abaroreflex stimulation process. At 1917, respiration is compared to atarget parameter. Baroreflex stimulation is increased at 1918 ifrespiration is below the target and is decreased at 1919 if respirationis above the target. According to various embodiments, the stimulationis not changed if the respiration falls within a blanking window.Various embodiments use memory to provide a hysteresis effect tostabilize the applied stimulation and the baroreflex response.Additionally, in various embodiments, the respiration target is modifiedduring the therapy based on various factors such as the time of day oractivity level. At 1920, it is determined whether to continue with thebaroreflex therapy algorithm based on, for example, sensed parameters orthe receipt of an event interrupt. If the baroreflex algorithm is tocontinue, then the process returns to 1917 where respiration is againcompared to a target parameter; else the baroreflex algorithm isdiscontinued at 1921.

Modulation of Neural Stimulation (e.g. Baroreflex Stimulation) Based onCircadian Rhythm

An aspect of the present subject matter relates to a method forstimulating the baroreflex in hypertension patients so as to mimic thenatural fluctuation in blood pressure that occurs over a 24-hour period.Reflex reduction in hypertension is achieved during long-termbaroreceptor stimulation without altering the intrinsic fluctuation inarterial pressure. According to various embodiments, an implantabledevice is designed to stimulate baroreceptors in the carotid sinus,pulmonary artery, or aortic arch using short, high-frequency bursts(such as a square wave with a frequency within a range fromapproximately 20-150 Hz), for example. Some embodiments directlystimulate the carotid sinus nerve, aortic nerve or vagus nerve with acuff electrode. However, the bursts do not occur at a constant rate.Rather the stimulation frequency, amplitude, and/or burst frequencyrises and falls during the day mimicking the natural circadian rhythm.

Thus, various embodiments of a NS device accounts for naturalfluctuations in arterial pressure that occur in both normal andhypertensive individuals. Aside from activity-related changes in meanarterial pressure, subjects also exhibit a consistent fluctuation inpressure on a 24-hour cycle. A device which provides periodicbaroreceptor stimulation mimics the intrinsic circadian rhythm, allowingfor reflex inhibition of the sympathetic nervous system and reducedsystemic blood pressure without disturbing this rhythm. The presentsubject matter provides a pacing protocol which varies the baroreceptorstimulation frequency/amplitude in order to reduce mean arterialpressure without disturbing the intrinsic circadian rhythm.

FIGS. 20A-20E illustrate circadian rhythm. FIG. 20A illustrates thecircadian rhythm associated with mean arterial pressure for 24 hoursfrom noon to noon; FIG. 20B illustrates the circadian rhythm associatedwith heart rate for 24 hours from noon to noon; FIG. 20C illustrates thecircadian rhythm associated with percent change of stroke volume (SV %)for 24 hours from noon to noon; FIG. 20D illustrates the circadianrhythm associated with the percent change of cardiac output (CO) for 24hours from noon to noon; and FIG. 20E illustrates the circadian rhythmassociated with percent change of total peripheral resistance (TPR %),an index of vasodilation, for 24 hours from noon to noon. Variousembodiments graph absolute values, and various embodiments graph percentvalues. In these figures, the shaded portion represents night hours fromabout 10 PM to 7 AM, and thus represents rest or sleep times. Referringto FIGS. 20A and 20B, for example, it is evident that both the meanarterial pressure and the heart rate are lowered during periods of rest.A higher blood pressure and heart rate can adversely affect rest.Additionally, a lower blood pressure and heart rate during the day canadversely affect a person's level of energy.

Various embodiments of the present subject matter modulate baroreflexstimulation using a pre-programmed template intended to match thecircadian rhythm for a number of subjects. Various embodiments of thepresent subject matter generate a template customized to match asubject.

FIG. 21 illustrates a method for modulating baroreceptor stimulationbased on circadian rhythm, according to various embodiments of thepresent subject matter, using a customized circadian rhythm template.The illustrated method 2122 senses and records parameters related tohypertension at 2123. Examples of such parameters include heart rate andmean arterial pressure. At 2124, a circadian rhythm template isgenerated based on these recorded parameters. At 2125, the baroreflexstimulation is modulated using the circadian rhythm template generatedin 2124.

The above-described embodiment refer to modulation of baroreceptorstimulation based on circadian rhythm. Neural stimulation, in general,can be modulated based on circadian rhythm. For example, a clock can beused to approximate times of low activity (when patient is expected tobe resting). Neural stimulation is increased during the expected resttime and turned off or reduced at other times. In some embodiments, theactivity monitor generates the circadian rhythm templates, which arethen applied to the neural stimulation schedule. According to variousembodiments, the circadian rhythm modulates the rules for adjusting theneural stimulation to adjust the neural stimulation intensity moreaggressively during one period of a day, and less aggressively duringanother period of the day. For example, more intense neural stimulationlevels (e.g. levels 3 and 4) can be mapped to given activity levels(e.g. levels n-1 and n) during a first period of time during the day,and less intense neural stimulation levels (e.g. levels 1 and 2) can bemapped to the given activity levels (e.g. levels n-1 and n) during asecond period of time during the day. In some embodiments that adjustneural stimulation intensity proportionally as a function of adifference x between the sensed activity and a reference, a less intensefunction (f₁(x)) can be used during a first period of time during theday, and a more intense function (f₂(x)) can be used during a secondperiod of time during the day. For example, some embodiments moreaggressively reduce neural stimulation intensity with increased activityduring the day, but less aggressively reduce neural stimulation withincreased activity at night.

Modulation of Neural Stimulation (e.g. Baroreflex Stimulation) toProvide Desired Cardiac Output

An aspect of the present subject matter relates to an implantablemedical device that provides NS therapy to lower systemic blood pressureby stimulating the baroreflex, and further provides cardiac pacingtherapy using a cardiac pacing lead for rate control. Baroreflexstimulation and cardiac pacing occurs in tandem, allowing blood pressureto be lowered without sacrificing cardiac output.

According to various embodiments, a baroreflex stimulator communicateswith a separate implantable CRM device, and uses the existing pacinglead. In various embodiments, baroreflex stimulation occurs throughbaroreceptors in the pulmonary artery, carotid sinus, or aortic archwith an electrode placed in or adjacent to the vessel wall. In variousembodiments, afferent nerves such as the aortic nerve, carotid sinusnerve, or vagus nerve are stimulated directly with a cuff electrode.

Baroreflex stimulation quickly results in vasodilation, and decreasessystemic blood pressure. To compensate for the concurrent decrease incardiac output, the pacing rate is increased during baroreflexstimulation. The present subject matter allows blood pressure to begradually lowered through baroreflex stimulation while avoiding the dropin cardiac output that otherwise accompanies such stimulation bycombining baroreflex stimulation with cardiac pacing, allowing animplantable device to maintain cardiac output during blood pressurecontrol.

FIG. 22A-B illustrate methods for modulating baroreceptor stimulationbased on a cardiac output parameter, according to various embodiments ofthe present subject matter. FIG. 22A illustrates one embodiment formodulating baroreceptor stimulation based on a cardiac output parameter.In the illustrated process 2226A, it is determined whether baroreflexstimulation is being applied at 2227. If baroreflex stimulation is notbeing applied, the present subject matter implements the appropriatepacing therapy, if any, at 2228 with the appropriate pacing rate. Ifbaroreflex stimulation is not being applied, the present subject matterimplements a pacing therapy at 2229 with a higher pacing rate tomaintain cardiac output.

FIG. 22B illustrates one embodiment for modulating baroreceptorstimulation based on a cardiac output parameter. In the illustratedprocess 2226B, baroreflex stimulation is applied at 2230, and it isdetermined whether the cardiac output is adequate at 2231. Upondetermining that the cardiac output is not adequate, the pacing rate isincreased at 2232 to maintain adequate cardiac output.

According to various embodiments, an existing pacing rate is increasedby a predetermined factor during baroreflex stimulation to maintaincardiac output. In various embodiments, a pacing rate is initiatedduring baroreflex stimulation to maintain cardiac output. Modulatingbaroreflex stimulation to provide desired cardiac output can beimplemented with atrial and ventricular rate control, AV delay control,resynchronization, and multisite stimulation. Alternatively, the strokevolume may be monitored by right ventricular impedance using electrodeswithin the right ventricular cavity or by left ventricular impedanceusing electrodes within or spanning the left ventricular cavity, and thepacing rate may be increased using application of neural stimulation tomaintain a fixed cardiac output.

Modulation of Baroreflex Stimulation To Remodel Stiffening Process

Aspects of the present subject matter involve a method for baroreflexstimulation, used by an implantable NS device, to lower systemic bloodpressure in patients with refractory hypertension. A baroreflexstimulation algorithm gradually increases baroreflex stimulation toslowly adjust blood pressure towards a programmable target. Thisalgorithm prevents the central nervous system from adapting to aconstant increased level of baroreflex stimulation, which ordinarilyattenuates the pressure-lowering effect. In addition, the gradual natureof the blood pressure change allows the patient to better tolerate thetherapy, without abrupt changes in systemic blood pressure and cardiacoutput.

The present subject matter provides a specific algorithm or processdesigned to prevent central nervous system adaptation to increasedbaroreflex stimulation, to slowly decrease blood pressure levels withtime to enable for the reversion of the arterial stiffening processtriggered by the previous hypertensive state present in the patient, andto prevent cardiac output decreases during baroreceptor stimulation. Itis expected that, with time, the arterial system reverse remodels thestiffening process that was started by the previously presenthypertension. The slow and progressive lowering of the mean/median bloodpressure enables the slow reversion of this stiffening process throughthe reverse remodeling. Blood pressure is reduced without compromisingcardiac output in the process, thus avoiding undesired patient symptoms.

In various embodiments, the device stimulates baroreceptors in thepulmonary artery, carotid sinus, or aortic arch with an electrode placedin or adjacent to the vessel wall. In various embodiments afferentnerves such as the aortic nerve, carotid sinus nerve, or vagus nerve arestimulated directly with a cuff electrode. The stimulated baroreflexquickly results in vasodilation, and a decrease in systemic bloodpressure. However, rather than stimulating the baroreflex at a constant,elevated level, the device of the present subject matter initiallystimulates at a slightly increased level, and then gradually increasesthe stimulation over a period of weeks or months, for example. The rateof change is determined by the device based on current and targetarterial pressure. In various embodiments, the system determines therate of change based on direct or indirect measurements of cardiacoutput, to ensure that the decrease in pressure is not occurring at theexpense of a decreased cardiac output. In various embodiments, the rateof baroreflex stimulation is not constant but has a white noise typedistribution to more closely mimic the nerve traffic distribution. Bymimicking the nerve traffic distribution, it is expected that thebaroreflex is more responsive to the stimulation, thus lowering thethreshold for stimulating the baroreflex.

FIG. 23 illustrates a method for modulating baroreceptor stimulation toreverse remodel stiffening, according to various embodiments of thepresent subject matter. A baroreflex event trigger occurs at 2333. Thistrigger includes any event which initiates baroreflex stimulation,including the activation of an AHT device. At 2334, an algorithm isimplemented to increase baroreflex stimulation by a predetermined rateof change to gradually lower the blood pressure to a target pressure inorder to reverse remodel the stiffening process. At 2335, it isdetermined whether to continue with the baroreflex stimulationalgorithm. The algorithm may be discontinued at 2336 based on an eventinterrupt, sensed parameters, and/or reaching the target blood pressure,for example. At 2337, it is determined whether the cardiac output isacceptable. If the cardiac output in not acceptable, at 2338 the rate ofchange for the baroreflex stimulate is modified based on the cardiacoutput.

Baroreflex Stimulation to Treat Myocardial Infarction

Following a myocardial infarction, myocytes in the infarcted region dieand are replaced by scar tissue, which has different mechanical andelastic properties from functional myocardium. Over time, this infarctedarea can thin and expand, causing a redistribution of myocardialstresses over the entire heart. Eventually, this process leads toimpaired mechanical function in the highly stressed regions and heartfailure. The highly stressed regions are referred to as being heavily“loaded” and a reduction in stress is termed “unloading.” A device totreat acute myocardial infarction to prevent or reduce myocardial damageis desirable.

An aspect of the present subject matter relates to an implantable devicethat monitors cardiac electrical activity. Upon detection of amyocardial infarction, the device electrically stimulates thebaroreflex, by stimulating baroreceptors in or adjacent to the vesselwalls and/or by directly stimulating pressure-sensitive nerves.Increased baroreflex stimulation compensates for reduced baroreflexsensitivity, and improves the clinical outcome in patients following amyocardial infarction. An implantable device (for example, a CRM device)monitors cardiac electrical activity. Upon detection of a myocardialinfarction, the device stimulates the baroreflex. Some embodiments ofthe device stimulate baroreceptors in the pulmonary artery, carotidsinus, or aortic arch with an electrode placed in or adjacent to thevessel wall. In various embodiments, afferent nerves such as the aorticnerve are stimulated directly with a cuff electrode, or with a leadintravenously placed near the afferent nerve. Afferent nerves such asthe carotid sinus nerve or vagus nerve are stimulated directly with acuff electrode, or with a lead intravenously placed near the afferentnerve. In various embodiments, a cardiac fat pad is stimulated using anelectrode screwed into the fat pad, or a lead intravenously fed into avessel or chamber proximate to the fat pad.

Baroreflex stimulation quickly results in vasodilation, and a decreasein systemic blood pressure. This compensates for reduced baroreflexsensitivity and reduces myocardial infarction. According to variousembodiments, systemic blood pressure, or a surrogate parameter, aremonitored during baroreflex stimulation to insure that an appropriatelevel of stimulation is delivered. Some aspects and embodiments of thepresent subject matter provides baroreflex stimulation to preventischemic damage following myocardial infarction.

FIGS. 24A-24B illustrate a system and method to detect myocardialinfarction and perform baropacing in response to the detected myocardialinfarction, according to various embodiments of the present subjectmatter. FIG. 24A illustrates a system that includes a myocardialinfarction detector 2439 and a baroreflex or baroreceptor stimulator2440. A myocardial infarction can be detected using anelectrocardiogram, for example. For example, a template can be comparedto the electrocardiogram to determine a myocardial infarction. Anotherexample detects changes in the ST segment elevation to detect myocardialinfarction. In various embodiments, the detector 2439 and stimulator2440 are integrated into a single implantable device such as in an AHTdevice or a CRM device, for example. In various embodiments, thedetector 2439 and stimulator 2440 are implemented in separateimplantable devices that are adapted to communicate with each other.

FIG. 24B illustrates a method to detect myocardial infarction andperform baropacing in response to the detected myocardial infarction,according to various embodiments of the present subject matter. At 2441,it is determined whether a myocardial infarction has occurred. Upondetermining that a myocardial infarction has occurred, the baroreflex isstimulated at 2442. For example, in various embodiments, thebaroreceptors in and around the pulmonary artery are stimulated using alead fed through the right atrium and the pulmonary valve and into thepulmonary artery. Other embodiments stimulate other baroreceptor sitesand pressure sensitive nerves. Some embodiments monitor the systemicblood pressure or a surrogate parameter at 2443, and determines at 2444if the stimulation should be adjusted based on this monitoring. If thestimulation is to be adjusted, the baroreflex stimulation is modulatedat 2445. Examples of modulation include changing the amplitude,frequency, burst frequency and/or waveform of the stimulation.

Neural stimulation, such as baroreflex stimulation, can be used tounload after a myocardial infarction. Various embodiments use an acutemyocardial infarction detection sensor, such as an ischemia sensor,within a feedback control system of an NS device. However, a myocardialinfarction detection sensor is not required. For example, a stimulationlead can be implanted after a myocardial infarction. In variousembodiments, the stimulation lead is implanted through the right atriumand into the pulmonary artery to stimulate baroreceptors in and aroundthe pulmonary artery. Various embodiments implant stimulation cuffs orleads to stimulate afferent nerves, electrode screws or leads tostimulate cardiac fat pads, and leads to stimulate other baroreceptorsas provided elsewhere in this disclosure.

Electrical pre-excitation of a heavily loaded region will reduce loadingon this region. This pre-excitation may significantly reduce cardiacoutput resulting in sympathetic activation and an increase in globalstress, ultimately leading to deleterious remodeling of the heart. Thisprocess may be circumvented by increased neural stimulation to reducethe impact of this reflex. Thus, activation of the parasympatheticnervous system during pre-excitation may prevent the undesirableside-effects of unloading by electrical pre-excitation.

One of ordinary skill in the art will understand that, the modules andother circuitry shown and described herein can be implemented usingsoftware, hardware, and combinations of software and hardware. As such,the term module is intended to encompass software implementations,hardware implementations, and software and hardware implementations.

The methods illustrated in this disclosure are not intended to beexclusive of other methods within the scope of the present subjectmatter. Those of ordinary skill in the art will understand, upon readingand comprehending this disclosure, other methods within the scope of thepresent subject matter. The above-identified embodiments, and portionsof the illustrated embodiments, are not necessarily mutually exclusive.These embodiments, or portions thereof, can be combined. For example,various embodiments combine two or more of the illustrated processes.Two or more sensed parameters can be combined into a composite parameterused to provide a desired neural stimulation (NS) or anti-hypertension(AHT) therapy. In various embodiments, the methods provided above areimplemented as a computer data signal embodied in a carrier wave orpropagated signal, that represents a sequence of instructions which,when executed by a processor cause the processor to perform therespective method. In various embodiments, methods provided above areimplemented as a set of instructions contained on a computer-accessiblemedium capable of directing a processor to perform the respectivemethod. In various embodiments, the medium is a magnetic medium, anelectronic medium, or an optical medium.

Although specific embodiments have been illustrated and describedherein, it will be appreciated by those of ordinary skill in the artthat any arrangement which is calculated to achieve the same purpose maybe substituted for the specific embodiment shown. This application isintended to cover adaptations or variations of the present subjectmatter. It is to be understood that the above description is intended tobe illustrative, and not restrictive. Combinations of the aboveembodiments as well as combinations of portions of the above embodimentsin other embodiments will be apparent to those of skill in the art uponreviewing the above description. The scope of the present subject mattershould be determined with reference to the appended claims, along withthe full scope of equivalents to which such claims are entitled.

1. A system for providing neural stimulation to a neural target in anautonomic nervous system of a patient for a heart failure therapy to thepatient, comprising: a motion monitor configured to sense motion of thepatient and provide a signal indicative of a sensed motion level,wherein the motion monitor is configured to sense an unintended motioncaused by the neural stimulation; a physiological activity monitorconfigured to sense a physiological activity of the patient that isdifferent than the sensed motion of the patient, wherein thephysiological activity monitor is configured to provide a signalindicative of a sensed physiological activity level; an electrodeconfigured for use to deliver the neural stimulation to the neuraltarget; a neural stimulator, including a pulse generator configured todeliver a neural stimulation signal through the electrode to provide theneural stimulation to the neural target for the heart failure therapy,wherein the pulse generator is configured to deliver the neuralstimulation signal as a series of pulses with different programmed burstpatterns for different stimulation intensity levels; and a modulatorconfigured to modulate the neural stimulation signal to change anintensity level of the neural stimulation; a controller configured tostore a mapping of a plurality of physiological activity levels and aplurality of motion levels for the unintended motion caused by theneural stimulation to a plurality of neural stimulation intensitylevels, wherein the controller is configured to receive both the signalindicative of the physiological activity level and the signal indicativeof the sensed motion level and to control the modulator to deliver theneural stimulation at intensity levels mapped to the sensedphysiological activity level and the sensed motion level.
 2. The systemof claim 1, wherein a given sensed motion level is mapped to at least afirst neural stimulation intensity level and a second neural stimulationintensity level, and wherein the controller is configured to deliver theneural stimulation at the first neural stimulation intensity level forthe given sensed motion level and a first sensed physiological activitylevel, and to deliver the neural stimulation at the second neuralstimulation intensity level for the given sensed motion level at asecond sensed physiological activity level .
 3. The system of claim 1,wherein the motion monitor includes an accelerometer.
 4. The system ofclaim 1, wherein the motion monitor is adapted to use electromyography(EMG) to evaluate muscle movement.
 5. The system of claim 1, wherein thephysiological activity monitor includes at least one monitor selectedfrom the group of physiological activity monitors consisting of: a heartrate monitor configured to sense heart rate of the patient and toprovide a signal indicative of a sensed heart rate level; a minuteventilation monitor configured to sense minute ventilation of thepatient and to provide a signal indicative of a sensed minuteventilation level; a stroke volume monitor configured to sense strokevolume of the patient and to provide a signal indicative of a sensedstroke volume level; a respiration rate monitor configured to senserespiration rate of the patient and to provide a signal indicative of asensed respiration rate level; a tidal volume monitor configured tosense tidal volume of the patient and to provide a signal indicative ofa sensed tidal volume level; a nerve activity monitor configured tosense nerve activity of the patient and to provide a signal indicativeof a sensed nerve activity level; a blood pressure monitor configured tosense blood pressure of the patient and to provide a signal indicativeof a sensed blood pressure level; a cardiac output monitor configured tosense cardiac output of the patient and to provide a signal indicativeof a sensed cardiac output level; or an accelerometer or EMG configuredto monitor patient activity in addition to patient motion.
 6. The systemof claim 1, wherein the modulator is configured to determine adifference between at least one reference parameter and at least onesensed motion parameter to determine the sensed motion level.
 7. Thesystem of claim 6, wherein the mapping of the plurality of motion levelsis in proportion to the difference.
 8. The system of claim 6, whereinthe modulator is configured to dynamically adjust the at least onereference parameter based on sensed motion over a period of time.
 9. Thesystem of claim 1, wherein the pulse generator and the modulator areadapted to provide the neural stimulation signal when the sensedphysiological activity level is below a threshold and withhold theneural stimulation signal when the sensed physiological activity levelis above the threshold.
 10. The system of claim 1, wherein thestimulation signal has an amplitude, and the modulator includes amodulator to modulate the amplitude based on the signal indicative ofthe sensed motion level and the sensed physiological activity level. 11.The system of claim 1, wherein the stimulation signal has a frequency,and the modulator includes a modulator to modulate the frequency basedon the signal indicative of the sensed motion level and the sensedphysiological activity level.
 12. The system of claim 1, wherein thepulse generator is adapted to generate a neural stimulation pulse train,and the modulator includes a modulator to change a duration of a neuralstimulation pulse train based on the signal indicative of the sensedmotion level and the sensed physiological activity level.
 13. The systemof claim 1, further comprising an implantable medical device, whereinthe implantable medical device includes the motion monitor, thephysiological activity monitor, and the neural stimulator.
 14. Thesystem of claim 1, further comprising an implantable neural stimulator(NS) device and an implantable cardiac stimulator, wherein theimplantable NS device includes the neural stimulator and the implantablecardiac stimulator includes the motion monitor and the physiologicalactivity monitor.
 15. The system of claim 1, wherein the mapping of theplurality of motion levels to the plurality of neural stimulationintensity levels more aggressively reduces neural stimulation intensitywith increased physiological activity during a first time of day, butless aggressively reduces neural stimulation with increasedphysiological activity during a second time of day.
 16. A method forusing an implantable device to deliver a heart failure therapy to apatient, comprising: using the implantable device to sense unintendedmotion of the patient caused by the neural stimulation and identify asensed motion level for the sensed unintended motion, and to sensephysiological activity of the patient, different than the sensed motion,and identify a sensed physiological activity level; delivering the heartfailure therapy, wherein delivering the heart failure therapy includesdelivering neural stimulation through an electrode to a neural target inan autonomic nervous system of the patient using the implantable device;and determining a neural stimulation intensity level for the heartfailure therapy using a programmed mapping of a plurality of motionlevels and a plurality of physiological activity levels to a pluralityof neural stimulation intensity levels, wherein determining the neuralstimulation intensity level includes using the sensed motion level, thesensed physiological activity level, and the programmed mapping todetermine the neural stimulation intensity level of the neuralstimulation to be delivered for the motion level.
 17. The method ofclaim 16, further comprising comparing sensed motion to a referenceparameter and using the comparison to determine the motion level. 18.The method of claim 17, wherein using the comparison includesdetermining a difference between the reference parameter and the sensedmotion to determine the motion level.
 19. The method of claim 16,wherein delivering neural stimulation includes providing neuralstimulation when the physiological activity level is below a threshold,and not delivering the neural stimulation when the physiologicalactivity level is above the threshold.
 20. The method of claim 16,wherein the programmed mapping of the plurality of motion levels to theplurality of stimulation levels is configured to abate the undesiredmotion.
 21. The method of claim 16, wherein using the implantable deviceto sense unintended motion of the patient includes using anaccelerometer to sense motion.
 22. The method of claim 16, wherein usingthe implantable device to sense unintended motion of the patientincludes using an electromyography (EMG) to evaluate muscle movement.23. The method of claim 16, wherein using the implantable device tosense physiological activity of the patient includes: using a heart ratemonitor to sense heart rate of the patient and to provide a signalindicative of a sensed heart rate level; using a minute ventilationmonitor to sense minute ventilation of the patient and to provide asignal indicative of a sensed minute ventilation level; using a strokevolume monitor to sense stroke volume of the patient and to provide asignal indicative of a sensed stroke volume level; using a respirationrate monitor to sense respiration rate of the patient and to provide asignal indicative of a sensed respiration rate level; using a tidalvolume monitor to sense tidal volume of the patient and to provide asignal indicative of a sensed tidal volume level; using a nerve activitymonitor to sense nerve activity of the patient and to provide a signalindicative of a sensed nerve activity level; using a blood pressuremonitor to sense blood pressure of the patient and to provide a signalindicative of a sensed blood pressure level; using a cardiac outputmonitor to sense cardiac output of the patient and to provide a signalindicative of a sensed cardiac output level; or using an accelerometeror EMG to monitor patient activity in addition to patient motion.